tbuckley/cabot-search huggingface dataset:
Abstract 4071: Identification of myeloma-specific T cell receptors by functional single cell interaction analyses
Authors: Tim R. Wagner, Eren Boğa, Patrick Schmidt, Wolfram Osen, Michael Platten, Hartmut Goldschmidt, Marc S. Raab, Mirco J. Friedrich, Stefan B. Eichmüller
Journal: Cancer Research (2023)

Abstract Innovative immunotherapy approaches such as adoptive transfer of chimeric antigen receptor (CAR) T cells or tumor infiltrating lymphocytes (TILs) have shown great success in the treatment of solid tumors and hematological malignancies. Although treatment of multiple myeloma with CAR T cells can induce deep responses, relapses frequently occur due to antigen escape and limited CAR T cell persistence. TCR-engineered T cells may mediate sustained antitumor effects upon recognition of intracellular targets, thereby significantly increasing the range of relevant target antigens. In our project, we propose to identify T cell receptors (TCRs) specifically targeting autologous myeloma cells. Tumor-reactive T cells were identified using the Berkeley Lights Lightning platform, allowing simultaneous functional analysis of up to 1500 individual T cell/target cell interactions per run. Reactive T cells have been identified upon detection of secreted chemokines (IFNγ, TNFα, IL-2) and by measurement of CD137 surface expression. Tumor-reactive T cells showing various cytokine secretion patterns and CD137 expression profiles could be detected in each myeloma patient (7 to 26 of approx.1200 cells tested per patient). Individual tumor reactive T cells have been isolated for TCR sequencing. Recovered TCR genes will be cloned and overexpressed in autologous T cells for functional validation and analysis of tumor derived neoepitope specificity. In summary, we present a pipeline allowing identification of myeloma-recognizing T cells and recovery of bona fide tumor-reactive TCRs eligible for patient-individualized T cell therapy. Citation Format: Tim R. Wagner, Eren Boğa, Patrick Schmidt, Wolfram Osen, Michael Platten, Hartmut Goldschmidt, Marc S. Raab, Mirco J. Friedrich, Stefan B. Eichmüller. Identification of myeloma-specific T cell receptors by functional single cell interaction analyses. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4071.
Abstract 4280: Automatic identification of cancer cell-cell interfaces at the pixel level
Authors: Jie Zhou, Jan Martinek, Zichao Liu, Ali Foroughi Pour, Te-Chia Wu, Santhosh Sivajothi, Paul Robson, Karolina Palucka, Jeffrey Hsu-Min Chuang
Journal: Cancer Research (2023)

Abstract Deciphering cell-cell interactions is critical for understanding the role of the tumor immune microenvironment. Although multiplex imaging methods are increasingly used for spatial characterization of cell communities and tissue morphologies, quantification of the interface between contacting cells has been mostly unexplored. Here we design an unsupervised pixel-level clustering method that accurately detects the contacting interface between cells. First, we observed pixel-level clusters with cell type specific phenotypes including tumor, immune infiltrates and extracellular structures in two independent melanoma datasets using cytometry time-of-flight (CyTOF) imaging mass cytometry (IMC) images. More importantly, our pixel-level approach identified clusters with mixed phenotypes, which are demonstrated to be direct contacts between T cells and myeloid cells. Specifically, pixels in the interface clusters simultaneously express T cell (CD3+, CD4+ or CD8+) and myeloid cell (CD68+) phenotypic markers at comparable levels. Spatial mapping of the pixels in interface clusters shows that interface pixels are in the physical contact regions between T cells and myeloid cells. In addition, the abundance of T cell and myeloid cell interface clusters is correlated with positive response to immune checkpoint inhibitors (ICIs) (p&amp;lt;0.05). We also identified other clusters indicating interfaces between the stroma, tumor cells, and immune infiltrates. Our work enables reliable delineation of cell interactions at high resolution, and therefore can unravel new information about how cancer cells interact with their environment. Citation Format: Jie Zhou, Jan Martinek, Zichao Liu, Ali Foroughi Pour, Te-Chia Wu, Santhosh Sivajothi, Paul Robson, Karolina Palucka, Jeffrey Hsu-Min Chuang. Automatic identification of cancer cell-cell interfaces at the pixel level. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4280.
Abstract 2870: Inhibition of DNA methylation and histone deacetylation synergistically reprograms M2-polarized macrophages and inhibits tumor growth by upregulating miR-7083-5p
Authors: Poongkavithai Vadevoo Sri Murugan, Gunassekaran Gowri Rangaswamy, Byungheon Lee
Journal: Cancer Research (2023)

Abstract Reactivation of epigenetically suppressed miRs, in tumors, have become increasingly relevant in clinical practice. But less epigenetic studies have been performed on tumor associated M2 macrophages that plays a key role in the functional regulation of epithelial cancer development. In this study, we used 5-Aza-2’5’Aza-deoxycytidine (Aza) or decitabine (5-Aza) plus Trichostatin A (TSA) as epigenetic drugs to study the M2 macrophage modulation in the tumor microenvironment. Epigenetic therapy, not only modulated the M2 macrophages to a tumoricidal phenotype, but also strengthened the tumor immune surveillance and eventually attenuated tumor growth. In vitro studies on M2 macrophages, showed that these epigenetic modifiers, namely 5Aza+TSA, fine-tuned the M2 macrophages into a ‘no more tumor friendly’ phenotype. Using comparative miR profiling, we identified nearly 79 miRs that were upregulated in M2 macrophages after epigenetic drug treatment. Of all miRs, miR-7083-5p showed 32 fold upregulation in M2 after epigenetic therapy and csf2ra, a GM-CSF receptor that helps in IL3 and GM-CSF signaling to M2 polarization, and CD43,a leukocyte marker, were one two of the important genes targeted by this miR-7083-5p. Nevertheless, re-expression of miR-7083-5p in M2 Macrophages in vitro, modulated M2 Macrophage to an anti-tumor phenotype and 4T1 tumor tissues showed inversed correlation between the expression of miR-7083-5p and its target,csf2ra and CD43,implying the pathological relevance of targeting. Considering the vital role of M2-TAM in tumor growth and metastasis, epigenetic drug mediated reactivation of miRs in M2-TAM could act as a promising therapeutic approach in cancer treatment. Citation Format: Poongkavithai Vadevoo Sri Murugan, Gunassekaran Gowri Rangaswamy, Byungheon Lee. Inhibition of DNA methylation and histone deacetylation synergistically reprograms M2-polarized macrophages and inhibits tumor growth by upregulating miR-7083-5p [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2870.
Abstract 5536: Landscape and analysis of ERBB2 amplification and short variant mutations in large-scale Chinese patients with colorectal cancer
Authors: Zhiqin Chen, Shijun Yu, Yin Wu, Bei Zhang, Ding Zhang, Yong Gao, Ming Quan
Journal: Cancer Research (2023)

Abstract Background: Human epidermal growth factor receptor 2 (ERBB2) amplification is a rapidly emerging therapeutic target in CRC, in spite of a relatively low incidence. While ERBB2 amplification has been considered as a critical biomarker to predict the efficacy and safety of anti-ERBB2 therapy of CRC, its point mutation status is largely ambiguous.Methods: Blood or tissues samples from 2454 Chinese patients with CRC were collected, and the genomic landscape, clinical characteristics and genetic features of ERBB2 in these samples were retrospectively investigated using next-generation sequencing (NGS) analysis. Results: Of the 2454 colorectal cancer patients, 3.46% (85) carried ERBB2 amplification, 2.24% (55) carried ERBB2 mutation, and some patients harbored both ERBB2 amplification and point mutation at the same time. Microsatellite instability high (MSI-H) was found in approximately 32.7% (18/55) of patients with ERBB2-mutated CRC, but almost negative in ERBB2-amplified CRC. The median fold change of ERBB2 amplification was 30 (Range 4 to 245). Among the 16 mutation sites detected from 55 patients with ERBB2 point mutations, p.R678Q was the most common mutation site (28%), followed by p.V842I (24%) and p.S310F/Y (12%), which appeared to be slightly different from previous reports. ERBB2 mutation was more frequently found in CRC patients aged &amp;lt; 50 years. 50.9% of CRC patients with wild-type ERBB2 carried KRAS mutation, which was significantly higher than those with mutated ERBB2 (25.6%). A higher incidence of BRAF mutation was observed in patients with mutated-ERBB2 (8.5% vs. 2.3%). In addition, CRC patients with ERBB2 CNV showed a higher prevalence of TP53 mutation comparing with those with ERBB2 SNV (92.3% vs. 58.3%), while KRAS mutation exhibited a contrary trend (14.1% vs. 45.8%)Conclusions: The overall variation rate of ERBB2 is 5.4% in Chinese patients with CRC, which is accompanied by significantly different molecular pathological characteristics compared to patients with wild-type ERBB2, and different mutation types (CNV or SNV) display different molecular pathological characteristics. Citation Format: Zhiqin Chen, Shijun Yu, Yin Wu, Bei Zhang, Ding Zhang, Yong Gao, Ming Quan. Landscape and analysis of ERBB2 amplification and short variant mutations in large-scale Chinese patients with colorectal cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5536.
Abstract 618: CRISPR screening identifies the deubiquitylase ATXN3 as a PD-L1 positive regulator for tumor immune evasion
Authors: Shengnan Wang, Radhika Lyer, Deyu Fang
Journal: Cancer Research (2023)

Abstract Regulation of tumoral PD-L1 expression is critical to advance our knowledge in understating the tumor evasion of immunosurveillance and for improvement of antitumor immunotherapy. While several E3 ubiquitin ligases and ubiquitin-specific peptidases regulate PD-L1 protein stability, the deubiquitinases involved in PD-L1 transcription for cancer cell immune evasion have not been identified. Herein, we developed a CRISPR-based screening platform and identified ATXN3 as a top positive regulator for PD-L1 transcription. Analysis of TCGA database revealed a statistically significant positive correlation between ATXN3 and CD274 expression in more than 80% human cancers, indicating that ATXN3 is a positive regulator for PD-L1 transcription in broad spectra of human cancers. ATXN3 promotes PD-L1 transcription induced by multiple tumor microenvironmental (TME) factors including inflammatory cytokine IFN-γ and hypoxia through protecting their downstream transcription factors IRF1, STAT3 and HIF-2α. In addition, ATXN3 functions as a deubiquitinase of PD-L1 transcription factors YAP-1 and JunB, indicating ATNX3 promotes PD-L1 expression through multiple pathways. Targeted deletion of ATXN3 in cancer cells resulted in reduced PD-L1 expression and consequently enhanced antitumor immunity in mice, which are partially revised by reconstitution of PD-L1 expression. Further, tumoral ATXN3 suppression improves the preclinical efficacy of checkpoint blockade antitumor immunotherapy and partially dependent on CD8+ T cells. Importantly, ATXN3 expression is increased in human lung adenocarcinoma and melanoma and its levels are positively corelated with PD-L1 as well as its transcription factor IRF1 and HIF-2α. Collectively, our study identifies a previously unknown deubiquitinase ATXN3 as a positive regulator for PD-L1 transcription and provides a rationale for ATXN3 targeting in sensitizing checkpoint blockade antitumor immunotherapy. Citation Format: Shengnan Wang, Radhika Lyer, Deyu Fang. CRISPR screening identifies the deubiquitylase ATXN3 as a PD-L1 positive regulator for tumor immune evasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 618.
Abstract 5106: The addition of radiation therapy to simultaneous targeting of PD-1 and IL2Rβγ enhances antigen-specific CD8 T cell anti-tumor immunity in pancreatic cancer models
Authors: Maureen Hoen, Miles Piper, Laurel B. Darragh, Diemmy Nugyen, Jacob Gadwa, Maria Amann, Greta Durini, Michael Knitz, Benjamin Van Court, Tiffany Pham, Ross Kedl, Pablo Umana, Laura Codarri-Deak, Christian Klein, Angelo D’Alessandro, Sana D. Karam
Journal: Cancer Research (2023)

Abstract Although IL-2 has been shown to critically mediate NK and T cell effector functions, when used in clinical trials this cytokine has failed due to toxicity and severe side effects of the systemic treatment. Our lab has investigated the use of a next-generation IL-2 compound, murine PD1-IL2v, which consists of an anti-PD-1 antibody fused to a IL2-variant with abolished binding to IL2Rα. Previous work shows this molecule results in tumor-antigen specific T cell expansion and differentiation towards immune effectors. Here, we report for the first time that radiation therapy amplifies the anti-tumor effect observed with PD1-IL2v treatment of murine orthotopic models of local tumor growth and metastasis. This anti-tumor effect is correlated with increases in proliferative and polyfunctional CD8 T cells across tumor, lymph node, and blood compartments. Furthermore, using an OVA-antigen specific orthotopic model, we found that radiation in combination with PD1-IL2v treatment enhances infiltration and activation of antigen-specific CD8 T cells, which have been shown to be critical for immunotherapy clinical success. A portion of tumor-bearing mice treated with radiation and PD1-IL2v fully eradicated their primary tumors and tumor rechallenges, which we show correlates with increased markers of memory in CD8 T cells of these mice. To demonstrate the clinical relevance of these preclinical findings, we performed RNA sequencing on paired pancreatic adenocarcinoma (PDAC) patient tumor tissue samples prior to and following radiation. We observed enhanced IL2Rβ and IL2Rγ expression as well as IL2R signaling in PDAC-patient responders to radiation therapy compared to non-responders. In conclusion, the antigen-specific, lasting memory response to preclinical PDAC models demonstrated here provides rationale for the treatment of PDAC with a radiation and PD1-IL2v combination. Citation Format: Maureen Hoen, Miles Piper, Laurel B. Darragh, Diemmy Nugyen, Jacob Gadwa, Maria Amann, Greta Durini, Michael Knitz, Benjamin Van Court, Tiffany Pham, Ross Kedl, Pablo Umana, Laura Codarri-Deak, Christian Klein, Angelo D’Alessandro, Sana D. Karam. The addition of radiation therapy to simultaneous targeting of PD-1 and IL2Rβγ enhances antigen-specific CD8 T cell anti-tumor immunity in pancreatic cancer models. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5106.
Abstract 4070: Engineering TRAIL-expressing immune cells to target GI malignancies
Authors: Praveen R. Srinivasan, Shengliang Zhang, Wafik S. El-Deiry
Journal: Cancer Research (2023)

Abstract While adoptive cell therapies, such as chimeric antigen receptor (CAR) T cells, have had promising results in hematologic malignancies, their translation to solid tumors has been mostly unsuccessful. A significant limitation to use of adoptive cell therapy in solid tumors has been life-threatening off-target toxicities, including acute respiratory toxicity and cytokine release syndrome. The native T cell program releases a diverse range of toxic proteins upon activation, including interferons, interleukins, perforins, and granzymes. Rather than activate the native T-cell program, selective expression of tumor-targeting agents may be advantageous. TNF-related apoptosis-inducing ligand (TRAIL) is known to selectively target tumor cells with minimal toxicity to normal tissues. We therefore engineered Jurkat (a human CD4+ T cell leukemia cell line) and THP-1 (a human monocytic leukemia cell line) cells to constitutively express wild-type TRAIL using a third-generation lentivirus system. These cells killed multiple cell lines across colorectal and pancreatic cancer, thus representing a possible therapeutic strategy to target GI malignancies. Furthermore, the addition of the ferroptosis induced erastin enhanced cytotoxicity of TRAIL-engineered cells, suggesting that targeting ferroptosis in addition to apoptosis is a promising strategy for enhancing immune killing. Future work will focus on overcoming TRAIL resistance, tumor trafficking, and alteration of the tumor microenvironment. Citation Format: Praveen R. Srinivasan, Shengliang Zhang, Wafik S. El-Deiry. Engineering TRAIL-expressing immune cells to target GI malignancies. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4070.
Abstract 6029: Multi-omic landscape of squamous cell lung cancer
Authors: Paul Stewart, Ashley Lui, Eric Welsh, Dalia Ercan, Vanessa Rubio, Hayley Ackerman, Guohui Li, Bin Fang, Steven Eschrich, John Koomen, Elsa Flores, Eric Haura, Gina DeNicola
Journal: Cancer Research (2023)

Abstract Patients with squamous cell lung cancer (SCC) have high unmet medical need. Knowledge of these tumors is limited, and a lack of targetable genomic drivers means patients have few treatment options. To provide a detailed analysis on the influence of genomic alterations to proteome-level changes in SCC, we previously integrated DNA copy number, somatic mutations, RNA-sequencing, and expression proteomics in a cohort of 108 SCC patients. A major finding was identification of three proteomic subtypes, two of which made up the majority (87%) of tumors: the “Inflamed” subtype was enriched for B-cell rich tertiary lymphoid structures (TLS), and the “Redox” subtype was enriched for redox pathways and NFE2L2/KEAP1 alterations but had significantly less immune infiltration. We hypothesized these proteomic subtypes would give rise to distinct metabolic signatures. Therefore, we performed untargeted metabolomics on 87 tumors from the same cohort using chromatographic separation on a HILIC column, followed by analysis on a Q Exactive HF mass spectrometer. This analysis yielded 7,344 features corresponding to 7,072 unannotated metabolites and 272 identified metabolites. Glutathione, a key redox metabolite, was anticorrelated with immune score (R = -0.44, padj = 0.004) calculated from our transcriptomic data with the ESTIMATE algorithm, and glutathione was elevated in the Redox proteomic subtype (0.58 log2 ratio, padj = 9.87E-04). Consensus clustering was next used to identify novel metabolomic subtypes of SCC. Surprisingly, none of the five metabolomic subtypes we identified corresponded to proteomic subtype or NFE2L2/KEAP1 alteration (Fisher’s Exact test p-values &amp;gt; 0.05). The fifth subtype had 332 metabolites (26 identified) differentially expressed (&amp;gt; 1.5 fold-change, padj &amp;lt; 0.05) with ascorbate and aldarate metabolism as the top enriched pathway (padj = 3.36E-04). Interestingly, this fifth metabolomic subtype had significantly higher DNp63-alpha (p = 2.40E-05), a primary transcript of delta-N p63 that is known to promote non-small cell lung cancer. Ongoing integrative analyses across omic types will determine how p53, p63, and p73 transcripts influence these metabolomic subtypes, how these transcripts relate to the poor immune infiltration in some SCC tumors, and if these transcripts relate to novel metabolic vulnerabilities in SCC. Citation Format: Paul Stewart, Ashley Lui, Eric Welsh, Dalia Ercan, Vanessa Rubio, Hayley Ackerman, Guohui Li, Bin Fang, Steven Eschrich, John Koomen, Elsa Flores, Eric Haura, Gina DeNicola. Multi-omic landscape of squamous cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6029.
Abstract 4378: Risk factors for death in the emergency department for melanoma patients
Authors: Jayla Hsiung, Kamil Taneja, Karan Patel, Michael Diaz, Jared Wolfe, Eric M. Toloza
Journal: Cancer Research (2023)

Abstract Introduction: Many cancer deaths are related to melanoma. While there have been many studies that have identified risk factors for death in these patients, very few of them have analyzed the risk factors for death in melanoma patients in the emergency department (ED). Methods: We utilized the 2006-2012 Nationwide Emergency Department Sample to characterize melanoma patients who die in the ED. Multivariate logistic regression was used to identify patient and hospital characteristics that were significantly associated with a higher chance of death. A p-value ≤0.05 was considered significant. Results: From 2006 to 2012, 239,956 melanoma patients presented to the ED, and 2.1% of these melanoma patients died. Most melanoma patients who died in the ED were over the age of 70 years (60.0%), male (63.8%), Medicare beneficiaries (65.6%), of the highest income quartile (31.0%), presenting to a hospital in the South (35.3%), presenting to non-trauma hospitals (48.3%), and presenting to metropolitan non-teaching hospitals (43.4%). The most common reasons for patients who died upon presentation to the ED were a secondary malignancy (20.7%), septicemia (10.8%), acute cerebrovascular disease (7.5%), pneumonia (5.2%), and congestive heart failure (2.6%). The top 3 factors associated with high risk of death were septicemia (odds ratio (OR)=7.39, 95% confidence interval (CI)=5.79-9.43; p&amp;lt;0.001), acute cerebrovascular disease (OR=3.44, 95%CI=2.62-4.51; p&amp;lt;0.001), and age &amp;gt;70 years (OR=2.50, 95%CI=1.24-5.03; p=0.010). Table 1 lists all risk factors associated with a higher risk of death. Conclusion: Melanoma patients over the age of 70, with septicemia, acute cerebrovascular disease, or pneumonia, and of male sex are at higher risk for death in the ED. Clinicians should be aware of these risk factors when melanoma patients present to the ED. Risk Factors Associated with Death for Melanoma Patients in the Emergency Department Risk Factor Odds Ratio (95% Confidence Interval) p-value Septicemia 7.39 (5.79-9.43) &amp;lt;0.001 Acute Cerebrovascular Disease 3.44 (2.62-4.51) &amp;lt;0.001 Age &amp;gt;70 2.50 (1.24-5.03) 0.010 Charlson Comorbidity Index of 3 or More 2.32 (1.89-2.84) &amp;lt;0.001 Pneumonia 1.76 (1.27-2.45) 0.001 Charlson Comorbidity Index of 1 1.64 (1.40-1.93) &amp;lt;0.001 Charlson Comorbidity Index of 2 1.63 (1.31-2.03) &amp;lt;0.001 Medicaid 1.63 (1.19-2.23) 0.002 Metropolitan Teaching Hospital 1.33 (1.05-1.68) 0.017 Citation Format: Jayla Hsiung, Kamil Taneja, Karan Patel, Michael Diaz, Jared Wolfe, Eric M. Toloza. Risk factors for death in the emergency department for melanoma patients. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4378.